Bacterial meningitis remains a major cause of morbidity and mortality, with a high incidence of residual neurological impairment. Early diagnosis and immediate onset of adequate antimicrobial treatment are essential for the survival of patients with bacterial meningitis. However, establishing the diagnosis of bacterial meningitis represents a difficult task in most cases, since clinical signs of acute meningitis are non-specific, and laboratory examinations of cerebrospinal fluid (CSF) often do not accurately differentiate between bacterial and aseptic meningitis. Accurate differentiation between bacterial and aseptic (e.g., viral) meningitis is difficult as both are inflammatory diseases that elicit similar host defense responses and clinical symptoms. Differential diagnosis can be made on positive identification of the bacteria from the cerebrospinal fluid of the affected individual. Unfortunately, it may take several days to grow and identify the bacteria and 25% of the time culture results are negative or equivocal even though the patients have bacterial meningitis. Similar or greater error rates affect nearly every laboratory parameter used for diagnostic purposes.
Due to the beneficial effects of early therapy in bacterial meningitis, antibiotics are often started before etiologic diagnosis is established. As a consequence, a high number of patients with aseptic meningitis receive unnecessary antibiotic treatment, leading to unnecessary and/or prolonged hospitalization, an increased financial burden to the health care system, and exposure of the patient to nosocomial infections and disorders, as well as other hazards associated with hospitalization.
Few laboratory parameters in the cerebrospinal fluid determine bacterial meningitis with absolute certainty, such as positive cerebrospinal fluid culture and Gram staining. Although highly specific, these parameters show very low sensitivities and are therefore not useful in ruling out bacterial infection. In addition to microbiological analysis, non-specific parameters in the cerebrospinal fluid are commonly used for the differential diagnosis of bacterial versus aseptic meningitis, such as total and differential cerebrospinal fluid leukocyte count, cerebrospinal fluid protein and glucose concentrations, CSF/serum glucose ratio, cerebrospinal fluid lactate and C-reactive protein levels. However, the diagnostic value of these parameters remains controversial, since their range of distribution overlaps widely in aseptic and bacterial cerebrospinal fluid. The current tests for diagnosing bacterial meningitis take hours to days for completion and have significant false-positive rates. Polymerase chain reaction (PCR) can be employed, but only if specialized equipment and trained lab personnel are available, and the causative agent is in significant quantities in the spinal fluid. Hospital admission of aseptic meningitis patients is unnecessary, adds a significant financial burden to the health care system (estimated at $1-2B/yr.), and increases the risk of dangerous hospital-acquired infections. There is a critical need for an inexpensive rapid assay that can distinguish between bacterial meningitis and aseptic meningitis.
The present invention overcomes previous shortcomings in the art by providing methods and compositions for differentiating bacterial meningitis from aseptic meningitis in a subject by detecting changes in complement protein levels in CSF of the subject.